Disease relevance of Smpd1

• Acid sphingomyelinase deficient mice: a model of types A and B Niemann-Pick disease [1].
• Acid sphingomyelinase-deficient mice mimic the neurovisceral form of human lysosomal storage disease (Niemann-Pick disease) [2].
• PAF-mediated pulmonary edema: a new role for acid sphingomyelinase and ceramide [3].
• Our results identify acid sphingomyelinase and ceramide as possible therapeutic targets in acute lung injury [3].
• Previous studies provided evidence that MCA/129 fibrosarcomas and B16 melanomas grow 2- to 4-fold faster in acid sphingomyelinase (asmase)-deficient mice than in asmase(+/+) littermates and are resistant to single-dose irradiation due to inability to mount an apoptotic response in tumor microvascular endothelium [4].

High impact information on Smpd1

• Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiation-induced apoptosis [5].
• Comparison with p53 knockout mice revealed that acid sphingomyelinase-mediated apoptosis and p53-mediated apoptosis are likely distinct and independent [5].
• Acid sphingomyelinase knockout mice also expressed defects in radiation-induced ceramide generation and apoptosis in vivo [5].
• These genetic models provide definitive evidence for the involvement of acid sphingomyelinase in one form of stress-induced apoptosis [5].
• Types A and B Niemann-Pick disease (NPD) result from the deficient activity of acid sphingomyelinase (ASM) [1].

Chemical compound and disease context of Smpd1

• Mannose 6-phosphate receptor-mediated uptake is defective in acid sphingomyelinase-deficient macrophages: implications for Niemann-Pick disease enzyme replacement therapy [6].

Biological context of Smpd1

• In FADD-/- embryonic fibroblasts reconstituted by transfection with a FADD cDNA expression construct, the TNF responsiveness of A-SMase was restored [7].
• In contrast, A-SMase activity in the outer epidermis was unchanged, indicating that this enzyme is crucially involved in basal permeability barrier homeostasis [8].
• These results suggest that N-SMase and A-SMase control important yet dissociable and nonoverlapping pathways of TNF receptor signal transduction [9].
• Mice defective in spermiogenesis (Tnp1(-/-), Gmcl1(-/-), Asm(-/-)) showed wild-type mid-preleptotene and bouquet frequencies [10].
• The Niemann-Pick mouse might facilitate studies on the function of aSMase in the generation of ceramide as proposed second messenger in the intracellular signaling pathways and across the plasma membrane [2].

Anatomical context of Smpd1

• Ceramide-independent CD28 and TCR signaling but reduced IL-2 secretion in T cells of acid sphingomyelinase-deficient mice [11].
• The secreted enzymatic activity was insensitive to digestion with endoglycosidase H but it was stimulated by Zn2+, although to a limited extent compared to aSMase constitutively released by murine endothelial cells [12].
• Analysis of these animals showed their tissues had no detectable ASM activity, the blood cholesterol levels and sphingomyelin in the liver and brain were elevated, and atrophy of the cerebellum and marked deficiency of Purkinje cells was evident [1].
• Acidic sphingomyelinase (ASM) is necessary for fas-induced GD3 ganglioside accumulation and efficient apoptosis of lymphoid cells [13].
• We have analyzed lymphoblastoid cell lines derived from patients affected by Niemann Pick disease (NPD), an autosomal recessive disorder caused by loss-of-function mutations within the acidic sphingomyelinase (ASM) gene [13].

Associations of Smpd1 with chemical compounds

• Cathepsin D targeted by acid sphingomyelinase-derived ceramide [14].
• Phorbol esters together with the calcium ionophore A23187 fully reproduced thrombin action on aSMase release [12].
• Moreover, mannose receptor-mediated transfer of ASM into NPD lymphoblasts rescues their ability to transiently activate ASM, accumulate GD3, and rapidly undergo apoptosis after Fas cross-linking [13].
• Activation of acid sphingomyelinase and its inhibition by the nitric oxide/cyclic guanosine 3',5'-monophosphate pathway: key events in Escherichia coli-elicited apoptosis of dendritic cells [15].
• These proapoptotic responses were not only sensitive to inhibitors of sphingomyelinase, PKCzeta, or NADPH oxidases but also to ASM knockdown, bafilomycin, and DIDS, i.e. maneuvers largely preventing hyperosmolarity-induced endosomal acidification and/or ceramide formation [16].

Co-localisations of Smpd1

• Most A-SMase activity in hairless mice (hr(-/-)) was found in the outer epidermal cell layers and colocalized in the lamellar bodies with A-SMase and sphingomyelin [17].

Regulatory relationships of Smpd1

• Requirement of FADD for tumor necrosis factor-induced activation of acid sphingomyelinase [7].
• We previously demonstrated that the aspartate protease cathepsin D is activated by ceramide derived from acid sphingomyelinase [18].
• Addition of ASM to rat hepatocytes activated JNK and down-regulated CYP7A1 mRNA levels [19].
• In this paper we show that CD95-stimulation blocks CRAC and Ca(2+) influx in lymphocytes through the activation of acidic sphingomyelinase (ASM) and ceramide release [20].
• Caspase activity plays a crucial role in Dex-induced apoptosis and is downstream the aSMase activation in that inhibition of the early ceramide generation inhibits caspase activation and thymocyte death [21].

Other interactions of Smpd1

• In addition, interleukin-1-induced activation of A-SMase in FADD-deficient cells was unaltered [7].
• The results of this study suggest that FADD, in addition to its role in triggering a proapoptotic caspase cascade, is required for TNF-induced activation of A-SMase [7].
• The N-SMase activation domain is distinct from the death domain and incapable of induction of A-SMase, NF-kappaB, and cytotoxicity [22].
• We have used the recently established acid sphingomyelinase-deficient mouse line (asmase-/- mice) to evaluate the role of acid sphingomyelinase in the TNF-alpha-induced signal transduction pathway [23].
• Tumor necrosis factor alpha activates NF-kappaB in acid sphingomyelinase-deficient mouse embryonic fibroblasts [23].

Analytical, diagnostic and therapeutic context of Smpd1

• We have generated an acid sphingomyelinase (aSMase)-deficient mouse line by gene targeting [2].
• In vivo, intravenous injection of 3 microg/25 g mouse body weight of anti-Fas Jo2 antibody into aSMase(-/-) mice failed to affect hepatocyte apoptosis or mortality, whereas massive hepatocyte apoptosis and animal death occurred in wild type littermates [24].
• Biochemical, pathological, and clinical response to transplantation of normal bone marrow cells into acid sphingomyelinase-deficient mice [25].
• 2. Recombinant SCCE induced a significant decrease in the immunoblotting of both beta-GlcCer'ase or aSMase compared with control experiments performed in the absence of the active SCCE [26].
• Preimplantation diagnosis of a lysosomal storage disorder by in situ enzymatic activity: 'proof of principle' in acid sphingomyelinase-deficient mice [27].

References